Immune System PDF

Introduction and Overview of the Immune System By Dr. ATIF SAEED MOHAMMED Assistant Professor Immunology and Immunotherapy Department of Biology Introduction  What is Immunology? It is the study of the cellular and molecular events that occur aft...

Introduction and Overview of the Immune System By Dr. ATIF SAEED MOHAMMED Assistant Professor Immunology and Immunotherapy Department of Biology Introduction  What is Immunology? It is the study of the cellular and molecular events that occur after an organism encounters pathogens and other foreign macromolecules.  What is Immune System? It is the cells and molecules responsible for immunity. What is Immune Response? It is the collective and coordinated response to the introduction of foreign substances.  A brief History Egyptian hieroglyphics describe fever. The first mention of immunity was by Thucydides, in Athens, in 5 B.C. The first true manipulation of the immune system was by Edward Jenner in 1798 with the first successful vaccination against smallpox. Presently, immunological research is a mix of cell culture, recombinant DNA methodology, and protein biochemistry.  The immune system is able to generate an enormous variety of cells and molecules capable of specifically recognizing and eliminating an apparently limitless variety of foreign invaders. Functionally, an immune response can be divided into two related activities recognition and response. Highly specialized receptors present for discriminating between ”self” and “nonself” body components. The discrimination between “self” and “non-self” and the subsequent destruction and removal of foreign material is accomplished by the two arms of the immune system; 1) The innate (natural or nonspecific) immune system. 2) The adaptive (acquired or specific) immune system. These two systems perform many of their functions by cooperative interactions.  Immunity Innate immunity Adaptive immunity Humoral Cell-mediated Components Components Macrophages antigen presenting cells Granulocytes T-cells Natural killer cells B-cells Complement Antibodies Other chemicals: HCL, lysozyme Characteristics Characteristics * Action is immediate * Action requires days to develop * Response is non-specific * Response is specific * Response is not enhanced on * Response is enhanced on repeated exposure to pathogen repeated exposure to pathogen The Innate (Natural) Immune System  Overview of the innate immune system  Innate immunity is the first line of defense and it is active at the time of infection.  It consists of protective cellular (WBCs and derivatives) and biochemical components that are in place before infection and can respond rapidly (minutes - hours).  It is divided into two stages: 1- non-inflammatory reaction (body’s static defenses) skin, gastric pH, lysozyme in tears, saliva, mucous. 2- local inflammation promotes migration of phagocytes and plasma protein into infected tissues.  The phagocytes respond to surface structures present in large groups of microorganisms (peptidoglycan, mannose). A. Non-specific Barrier Immunity – First Line of Defense 1. Surface (physical) Barriers – intact skin, hair a. specialized membranes – mucus b. specialized structures 2. Antimicrobial substances – sweat, oil, saliva, stomach acid, lysozyme, enzymes. 3. Normal flora - competitors, inhibitors B. Nonspecific Cellular Defenses – Second Line of defense 1. Cellular Components – a. RBC's - 5 mill/cc = 99% b. WBC's - 5-9,000/cc i. PMN's-neutrophils - 55-60% ii. Lymphocytes - B and T's - 30-35% iii. Monocytes - phagocytes - 5-8% iv. Eosinophils - 2-4% v. Basophils - 0-1% c. Thrombocytes - platelets - 250 - 400,000/cc 2. Phagocytosis – Monocytes, neutrophils, eosinophils 3. Opsonisation by complement Role of Phagocytosis 1- Chemotaxis & attachment o Attraction by chemotactic Substances (microbes, inflamed tissues). o Attachment by receptors on surfaces of phagocytes (FcR, complement R, scavenger R, Toll-like R). 2- Ingestion o Phagocytes pseudopodia surround organism forming phagosome. o Opsonins and co-factors enhance phagocytosis. o Fusion with phag. granules and release digestive, toxic contents.  Role of Phagocytosis cont. 3- Killing (two microbicidal routes) o Oxygen dependent system (powerful microbicidal agents): Oxygen converted to superoxide, anion, hydrogen peroxide, activated oxygen and hydroxyl radicals. o Oxygen-independent system (anaerobic conditions): Digestion and killing by lysozyme. Lactoferrin, low pH, cationic proteins and hydrolytic and proteolytic enzymes.  Respiratory burst O2- dependent MPO-independent reactions G-6-P-dehydrogenase Pentose-P + NADPH Glucose + NADP+ NADPH oxidase NADP+ + O2 NADPH + O2 Cytochrome B - Superoxide dismutase 2O2 + 2H+ H2O2 + 1O2 - 2O2 + H2O2 OH* + OH- + 1O2 - Toxic compounds: superoxide anion O2 , hydrogen peroxide H2O2 , singlet oxygen 1O2 , hydroxyl radical OH*  Respiratory burst O2-dependent MPO-dependent reactions myeloperoxidase H2O2 + Cl- OCl- + H2O - 1O 2OCl + H2O 2 + Cl- + H2O Toxic compounds: hypochlorous acid OCl-, singlet oxygen 1O2  Respiratory burst Detoxification reactions - Superoxide dismutase H2O2 + O2 O2 + 2H+ Catalase H 2O + O 2 2H2O2  Acute Inflammation Resulting from Infection Inflammation is a nonspecific response of living tissue to localize and eliminate the injurious agent. The injury may be: - physical, - chemical, or - biological  The Inflammatory Response Specialized cells and serum proteins move from plasma to interstitial spaces to provide an immediate defense. The inflammatory cells include: o Phagocytes which destroy the invading organisms by phagcytosis followed by intracellular digestion. o Natural killer cells which limit infection by releasing compounds toxic to organisms. Serum components: Acute phase proteins (e.g. C- reactive protein). - C-reactive protein is produced by liver in response to tissue damage. - C-reactive protein binds to the cell walls of bacteria and activates the complement system resulting in the opsonization and lyses of pathogenic organisms.  The “four cardinal signs of inflammation” Rubor (redness), tumor (swelling), calor (heat), and dolor (pain). a fifth sign added later: functio laesa (loss of function). The cardinal signs of inflammation reflect the three major events of an inflammatory response: 1. Vasodilation—an increase in the diameter of blood vessels—of nearby capillaries occurs as the vessels that carry blood away from the affected area constrict, resulting in engorgement of the capillary network. The engorged capillaries are responsible for tissue redness (erythema) and an increase in tissue temperature. 2. An increase in capillary permeability facilitates an influx of fluid and cells. The fluid that accumulates (exudate) has a much high protein content, which contributes to tissue swelling (edema). 3. Influx of phagocytes. It is a multistep process that includes: - margination, - diapedesis or extravasation, - and, chemotaxis.  The accumulation of dead cells, digested material, and fluid forms a substance called pus.  Major events in the inflammatory response  Determinants recognized by the innate immune system Macrophage activation; Opsonization: Production of IFN secretion of Phagocytosis complement activation (antiviral) inflammatory cytokines PAMP= microbial PAMP= polyanions PAMP= dsRNA PAMP= LPS cell wall PRR= scavenger PRR= TLR3 PRR= TLR4 PRR= complement receptors PAMP= mannose- PAMP= U-rich ssRNA containing carbs PAMP= flagellin (viral) PRR= mannose- PRR= TLR5 PRR= TLR7 binding protein PAMP= CpG containing DNA PRR= TLR9  Immune response to damage  Dependent on what, where and how bad  Phased response with critical timing  Requires chemokine signaling, receptor binding, etc. B cells Cytotoxic T cells Helper T cells Mononuclear phagocytes neutrophils Days: 0 4 7 Weeks: 2 4 6 Summary of nonspecific host defenses The Adaptive (Acquired) Immune System Overview of the adaptive immune system Adaptive immunity is the later response of the immune system. It consists of cellular and biochemical defenses that are stimulated by exposure to pathogens and increase in magnitude and defense capabilities with each successive exposure to a particular pathogen. It has the capacity to remember an encounter with a pathogen.  Adaptive immunity displays four characteristic attributes:  Antigenic specificity permits it to distinguish subtle differences among antigens to the level of single amino acid.  Diversity allowing it to recognize billions of unique structures on foreign antigens.  Immunologic memory Once recognized and responded to an antigen, it exhibits immunologic memory; that is, a second encounter with the same antigen induces a heightened state of immune reactivity.  Self/nonself recognition normally responds only to foreign antigens. The ability to distinguish self from nonself and respond only to nonself molecules is essential, for the outcome of an inappropriate response to self molecules can be fatal. Through the carefully regulated interplay of adaptive and innate immunity, the two systems work together to eliminate a foreign invader.  An effective immune response involves two major groups of cells: T lymphocytes and antigen-presenting cells (APCs). Lymphocytes are one of many types of white blood cells produced in the bone marrow by the process of hematopoiesis. They leave the bone marrow, circulate in the blood and lymphatic systems, and reside in various lymphoid organs. Because they produce and display antigen-binding cell- surface receptors, lymphocytes mediate the defining immunologic attributes of specificity, diversity, memory, and self/nonself recognition. The two major populations of lymphocytes: B lymphocytes (B cells) and T lymphocytes (T cells).  B lymphocytes B lymphocytes mature within the bone marrow; when they leave it, each expresses a unique antigen-binding receptor on its membrane. This antigen-binding or B-cell receptor is a membrane- bound antibody molecule. When a naive B cell first encounters the antigen that matches its membrane-bound antibody, the binding of the antigen to the antibody causes the cell to divide rapidly; its progeny differentiate into memory B cells and effector B cells called plasma cells.  Memory B cells have a longer life span than naive cells, and they express the same membrane-bound antibody as their parent B cell. Plasma cells produce the antibody in a form that can be secreted and have little or no membrane-bound antibody. Although plasma cells live for only a few days, they secrete enormous amounts of antibody during this time. It has been estimated that a single plasma cell can secrete more than 2000 molecules of antibody per second. Secreted antibodies are the major effector molecules of humoral immunity.  T Lymphocytes T lymphocytes also arise in the bone marrow. T cells migrate to the thymus gland to mature. During its maturation within the thymus, the T cell comes to express a unique antigen-binding molecule, called the T-cell receptor, on its membrane. T-cell receptors can recognize only antigen that is bound to cell-membrane proteins called major histo- compatibility complex (MHC) molecules. There are two major types of MHC molecules: Class I MHC molecules, which are expressed by nearly all nucleated, and Class II MHC molecules, are expressed only by antigen-presenting cells.  When a naive T cell encounters antigen combined with a MHC molecule on a cell, the T cell proliferates and differentiates into memory T cells and various effector T cells. There are two well-defined subpopulations of T cells: T helper (Th) and T cytotoxic (TC) cells. T helper and T cytotoxic cells can be distinguished from one another by the presence of either CD4 or CD8 membrane glycoproteins on their surfaces. Effector cell secretes various growth factors known collectively as cytokines.  Cells that display foreign antigen complexed with a class I MHC molecule are called altered self-cells; these are targets of CTLs.  Four related but distinct cell-membrane molecules are responsible for antigen recognition by the immune system:  BCR  TCR  Class I MHC  Class II MHC  Processing and presentation of exogenous and endogenous antigens Thanks